Background— The molecular mechanism of increased background inward rectifier current ( I K1 ) in atrial fibrillation (AF) is not fully understood. We tested whether constitutively active acetylcholine (ACh)-activated I K,ACh contributes to enhanced basal conductance in chronic AF (cAF). Methods and Results— Whole-cell and single-channel currents were measured with standard voltage-clamp techniques in atrial myocytes from patients with sinus rhythm (SR) and cAF. The selective I K,ACh blocker tertiapin was used for inhibition of I K,ACh . Whole-cell basal current was larger in cAF than in SR, whereas carbachol (CCh)-activated I K,ACh was lower in cAF than in SR. Tertiapin (0.1 to 100 nmol/L) reduced I K,ACh in a concentration-dependent manner with greater potency in cAF than in SR (−logIC 50 : 9.1 versus 8.2; P <0.05). Basal current contained a tertiapin-sensitive component that was larger in cAF than in SR (tertiapin [10 nmol/L]-sensitive current at −100 mV: cAF, −6.7±1.2 pA/pF, n=16/5 [myocytes/patients] versus SR, −1.7±0.5 pA/pF, n=24/8), suggesting contribution of constitutively active I K,ACh to basal current. In single-channel recordings, constitutively active I K,ACh was prominent in cAF but not in SR (channel open probability: cAF, 5.4±0.7%, n=19/9 versus SR, 0.1±0.05%, n=16/9; P <0.05). Moreover, I K1 channel open probability was higher in cAF than in SR (13.4±0.4%, n=19/9 versus 11.4±0.7%, n=16/9; P <0.05) without changes in other channel characteristics. Conclusions— Our results demonstrate that larger basal inward rectifier K + current in cAF consists of increased I K1 activity and constitutively active I K,ACh . Blockade of I K,ACh may represent a new therapeutic target in AF.

SK channels are present in human atria where they participate in repolarization. SK2 and SK3 were down-regulated and had reduced functional importance in chronic AF. As SK current was not found to contribute substantially to the ventricular AP, pharmacological inhibition of SK channels may be a putative atrial-selective target for future antiarrhythmic drug therapy.

Background-Although downregulation of L-type Ca 2ϩ current (I Ca,L ) in chronic atrial fibrillation (AF) is an important determinant of electrical remodeling, the molecular mechanisms are not fully understood. Here, we tested whether reduced I Ca,L in AF is associated with alterations in phosphorylation-dependent channel regulation. Methods and Results-We used whole-cell voltage-clamp technique and biochemical assays to study regulation and expression of I Ca,L in myocytes and atrial tissue from 148 patients with sinus rhythm (SR) and chronic AF. Basal I Ca,L at ϩ10 mV was smaller in AF than in SR (Ϫ3.8Ϯ0.3 pA/pF, nϭ138/37 [myocytes/patients] and Ϫ7.6Ϯ0.4 pA/pF, nϭ276/86, respectively; PϽ0.001), though protein levels of the pore-forming ␣ 1c and regulatory ␤ 2a channel subunits were not different. In both groups, norepinephrine (0.01 to 10 mol/L) increased I Ca,L with a similar maximum effect and comparable potency. Selective blockers of kinases revealed that basal I Ca,L was enhanced by Ca 2ϩ /calmodulindependent protein kinase II in SR but not in AF. Norepinephrine-activated I Ca,L was larger with protein kinase C block in SR only, suggesting decreased channel phosphorylation in AF. The type 1 and type 2A phosphatase inhibitor okadaic acid increased basal I Ca,L more effectively in AF than in SR, which was compatible with increased type 2A phosphatase but not type 1 phosphatase protein expression and higher phosphatase activity in AF. Conclusions-In AF, increased protein phosphatase activity contributes to impaired basal I Ca,L . We propose that protein phosphatases may be potential therapeutic targets for AF treatment.